Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy

Abstract

Neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. Since some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO) we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine β-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons, and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.

Catechol-O-methyltransferase gene polymorphism and chronic human pain

“…If COMT activity is compromised, then DOPEGAL may accumulate, acting as a pain inducer. Unfortunately, some of the original results have been retracted [100], and the role of this intriguing nociceptive metabolite remains unclear.…”

“…A monoamine oxidase-dependent catecholamine metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), produces mechanical hyperalgesia [99]. DOPEGAL is metabolized by aldehyde reductase to 3,4-dihydroxyphenylglycol and is further O-methylated by COMT.…”

Diabetes-Causing Gene, Kruppel-Like Factor 11, Modulates the Antinociceptive Response of Chronic Ethanol Intake

“…Therefore, the increase in MAO A activity in Klf11 −/− mice may play a role in the reduced antinociceptive effects of chronic ethanol exposure in Klf11 −/− mice due to the increase in the production of the MAO A catecholamine metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) (Dina et al, 2008). DOPEGAL has been reported to produce hyperalgesia in a rat model given a short-term ethanol diet exposure and subsequent withdrawal (4-day fed/3-day off) (Dina et al, 2008).…”

“…Therefore, the increase in MAO A activity in Klf11 −/− mice may play a role in the reduced antinociceptive effects of chronic ethanol exposure in Klf11 −/− mice due to the increase in the production of the MAO A catecholamine metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) (Dina et al, 2008). DOPEGAL has been reported to produce hyperalgesia in a rat model given a short-term ethanol diet exposure and subsequent withdrawal (4-day fed/3-day off) (Dina et al, 2008). Since KLF11 has recently been reported to activate the expression of MAO A (Grunewald et al, 2012), the mechanism responsible for the slightly increase in MAO A activation in chronic ethanol-fed Klf11 −/− mice in the current study needs to be further investigated.…”

“…Studies have documented an involvement of these neurotransmitter systems in the regulation of pain (Zubieta et al, 2003). For instance, increases in MAO A catecholamine metabolites have been proposed to be involved in pain perception and MAO A inhibitors have been shown to reduce pain perception (Dina et al, 2008). …”